Generic Name: MIDAZOLAM HYDROCHLORIDE
Brand Name: Midazolam Hydrochloride
  • Substance Name(s):
  • MIDAZOLAM HYDROCHLORIDE

WARNINGS

Personnel and Equipment for Monitoring and Resuscitation Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that are equipped to provide continuous monitoring of respiratory and cardiac function.

Midazolam HCl syrup must only be administered to patients if they will be monitored by direct visual observation by a health care professional.

If midazolam HCl syrup will be administered in combination with other anesthetic drugs or drugs which depress the central nervous system, patients must be monitored by persons specifically trained in the use of these drugs and, in particular, in the management of respiratory effects of these drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

For deeply sedated patients, a dedicated individual whose sole responsibility is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Patients should be continuously monitored for early signs of hypoventilation, airway obstruction, or apnea with means for detection readily available (eg, pulse oximetry).

Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately.

The immediate availability of specific reversal agents (flumazenil) is highly recommended.

Vital signs should continue to be monitored during the recovery period.

Because midazolam can depress respiration [see CLINICAL PHARMACOLOGY] , especially when used concomitantly with opioid agonists and other sedatives [see DOSAGE AND ADMINISTRATION] , it should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway, and supporting ventilation.

Episodes of oxygen desaturation, respiratory depression, apnea, and airway obstruction have been occasionally reported following premedication (sedation prior to induction of anesthesia) with oral midazolam; such events are markedly increased when oral midazolam is combined with other central nervous system depressing agents and in patients with abnormal airway anatomy, patients with cyanotic congenital heart disease, or patients with sepsis or severe pulmonary disease.

Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including midazolam, and opioids may result in profound sedation, respiratory depression, coma and death.

If a decision is made to use midazolam concomitantly with opioids, monitor patients for respiratory depression and sedation [see PRECAUTIONS/Drug Interactions] .

Risk of Respiratory Adverse Events Serious respiratory adverse events have occurred after administration of oral midazolam, most often when midazolam was used in combination with other central nervous system depressants.

These adverse events have included respiratory depression, airway obstruction, oxygen desaturation, apnea, and rarely, respiratory and/or cardiac arrest [see BOX WARNING] .

When oral midazolam is administered as the sole agent at recommended doses respiratory depression, airway obstruction, oxygen desaturation, and apnea occur infrequently [see DOSAGE AND ADMINISTRATION] .

Prior to the administration of midazolam in any dose, the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation should be ensured.

Individualization of Dosage Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing central nervous system depression.

See DOSAGE AND ADMINISTRATION for complete information.

Other Adverse Events Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients.

Consideration should be given to the possibility of paradoxical reaction.

Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding.

Reversal of such responses with flumazenil has been reported in pediatric and adult patients.

Concomitant Use of Central Nervous System Depressants Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect.

Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.

Drug-Drug Interactions Coadministration of oral midazolam in patients who are taking ketoconazole and intraconazole, and saquinavir has been shown to result in large increases in Cmax and AUC of midazolam due to a decrease in plasma clearance of midazolam [see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Drug-Drug Interactions and PRECAUTIONS] .

Due to the potential for intense and prolonged sedation and respiratory depression, midazolam syrup should only be coadministered with these medications if absolutely necessary and with appropriate equipment and personnel available to respond to respiratory insufficiency.

Debilitation and Comorbidity Considerations Higher risk pediatric surgical patients may require lower doses, whether or not concomitant sedating medications have been administered.

Pediatric patients with cardiac or respiratory compromise may be unusually sensitive to the respiratory depressant effect of midazolam.

Pediatric patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction.

Patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly [see CLINICAL PHARMACOLOGY] .

Return to Cognitive Function Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours.

The decision as to when patients who have received midazolam HCl syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized.

Gross tests of recovery from the effects of midazolam HCl syrup [see CLINICAL PHARMACOLOGY] cannot be relied upon to predict reaction time under stress.

It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer.

Particular care should be taken to assure safe ambulation.

Neonatal Sedation and Withdrawal Syndrome Use of midazolam HCl syrup late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate ( see PRECAUTIONS: Pregnancy).

Monitor neonates exposed to midazolam HCl syrup during pregnancy or labor for signs of sedation and monitor neonates exposed to midazolam HCl syrup during pregnancy for signs of withdrawal; manage these infants accordingly.

Usage in Preterm Infants and Neonates Midazolam HCl syrup has not been studied in patients less than 6 months of age.

Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours.

The clinical significance of these findings is not clear.

However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see PRECAUTIONS; Pregnancy, Pediatric Use and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY] .

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects.

These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children and pregnant women needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other.

Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

DRUG INTERACTIONS

Drug Interactions Effect of Concomitant Use of Benzodiazepines and Opioids The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration.

Benzodiazepines interact at GABA A sites, and opioids interact primarily at mu receptors.

When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.

Monitor patients closely for respiratory depression and sedation.

Other CNS Depressants One case was reported of inadequate sedation with chloral hydrate and later with oral midazolam due to a possible interaction with methylphenidate administered chronically in a 2-year-old boy with a history of Williams syndrome.

The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate.

The sedative effect of midazolam HCl syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly opioids (e.g., morphine, meperidine, and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol.

Consequently, the dose of midazolam HCl syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response [see DOSAGE AND ADMINISTRATION] .

No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed.

Inhibitors of CYP3A4 Isozymes Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics).

Drugs such as diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, saquinavir, and verapamil were shown to significantly increase the C max and AUC of orally administered midazolam.

These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam.

Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam.

Caution is advised when midazolam HCl syrup is used concomitantly with these drugs.

Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated [see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Drug-Drug Interactions] .

Inducers of CYP3A4 Isozymes Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and cause a markedly decreased C max and AUC of oral midazolam in adult studies.

Although clinical studies have not been performed, phenobarbital is expected to have the same effect.

Caution is advised when administering midazolam HCl syrup to patients receiving these medications and if necessary dose adjustments should be considered.

OVERDOSAGE

Clinical Presentation Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma.

In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia.

Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur.

In severe overdosage cases, patients may develop respiratory depression and coma.

Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS: Dependence and Withdrawal Reactions).

Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.

Management of Overdose In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management.

Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with longterm benzodiazepine use and physical dependency.

The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy.

Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus).

If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage.

See the flumazenil injection Prescribing Information.

Consider contacting a poison center (1-800-221-2222) or a medical toxicologist for additional overdosage management recommendations.

DESCRIPTION

Midazolam is a benzodiazepine available as midazolam HCl syrup for oral administration.

Midazolam, a white to light yellow crystalline compound, is insoluble in water, but can be solubilized in aqueous solutions by formation of the hydrochloride salt in situ under acidic conditions.

Chemically, midazolam HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4 H -imidazo[1,5-a][1,4]benzodiazepine hydrochloride.

Midazolam hydrochloride has the molecular formula C 18 H 13 ClFN 3 ·HCl, a calculated molecular weight of 362.25 and the following structural formula: Each mL of the syrup contains midazolam hydrochloride equivalent to 2 mg midazolam compounded with artificial bitterness modifier, citric acid anhydrous, D&C Red #33, edetate disodium, glycerin, mixed fruit flavor, sodium benzoate, sodium citrate, sorbitol, and water; the pH is adjusted to 2.8 to 3.6 with hydrochloric acid.

Under the acidic conditions required to solubilize midazolam in the syrup, midazolam is present as an equilibrium mixture (shown below) of the closed ring form shown above and an open-ring structure formed by the acid-catalyzed ring opening of the 4,5-double bond of the diazepine ring.

The amount of open-ring form is dependent upon the pH of the solution.

At the specified pH of the syrup, the solution may contain up to about 40% of the open-ring compound.

At the physiologic conditions under which the product is absorbed (pH of 5 to 8) into the systemic circulation, any open-ring form present reverts to the physiologically active, lipophilic, closed-ring form (midazolam) and is absorbed as such.

The following chart below plots the percentage of midazolam present as the open-ring form as a function of pH in aqueous solutions.

As indicated in the graph, the amount of open-ring compound present in solution is sensitive to changes in pH over the pH range specified for the product: 2.8 to 3.6.

Above pH 5, at least 99% of the mixture is present in the closed-ring form.

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HOW SUPPLIED

Midazolam HCl Syrup is supplied as a clear, red to purplish-red, mixed fruit flavored syrup containing midazolam hydrochloride equivalent to 2 mg of midazolam/mL; each amber glass bottle of 118 mL of syrup is supplied with 1 press-in bottle adapter, 4 single-use, graduated, oral dispensers and 4 tip caps; 10 x bottle of 2.5 mL is supplied with 10 single-use, graduated, oral dispensers and 10 tip caps.

NDC 0574-0150-04 Bottle of 118 mL.

NDC 0574-0150-25 10 x Bottle of 2.5 mL.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature.]

GERIATRIC USE

Geriatric Use The safety and efficacy of this product have not been fully studied in geriatric patients.

Therefore, there are no available data on a safe dosing regimen.

One study in geriatric subjects, using midazolam 7.5 mg as a premedicant prior to general anesthesia, noted a 60% incidence of hypoxemia (pO 2 <90% for over 30 seconds) at sometime during the operative procedure versus 15% for the nonpremedicated group.

Until further information is available it is recommended that this product should not be used in geriatric patients.

Use in Patients With Heart Disease Following oral administration of 7.5 mg of midazolam to adult patients with congestive heart failure, the half-life of midazolam was 43% higher than in control subjects.

One study suggests that hypercarbia or hypoxia following premedication with oral midazolam might pose a risk to children with congenital heart disease and pulmonary hypertension, although there are no known reports of pulmonary hypertensive crisis that had been triggered by premedication.

In the study, 22 children were premedicated with oral midazolam (0.75 mg/kg) or IM morphine plus scopolamine prior to elective repair of congenital cardiac defects.

Both premedication regimens increased PtcCO 2 and decreased SpO 2 and respiratory rates preferentially in patients with pulmonary hypertension.

INDICATIONS AND USAGE

Midazolam HCl syrup is indicated for use in pediatric patients for sedation, anxiolysis and amnesia prior to diagnostic, therapeutic or endoscopic procedures or before induction of anesthesia.

Midazolam HCl syrup is intended for use in monitored settings only and not for chronic or home use [see WARNINGS] .

PEDIATRIC USE

Pediatric Use Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as Midazolam Hydrochloride Syrup 2 mg/mL, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis.

Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss.

Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory.

The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data.

[See WARNINGS; Pediatric Neurotoxicity, PRECAUTIONS; Pregnancy, and Pediatric Use, and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY] .

PREGNANCY

Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including midazolam HCl syrup, during pregnancy.

Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/.

Risk Summary Infants born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and Clinical Considerations ) .

Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data ).

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S.

general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in neonates.

Monitor neonates exposed to midazolam HCl syrup during pregnancy and labor for signs of sedation, respiratory depression, hypotonia, and feeding problems.

Monitor neonates exposed to midazolam HCl syrup during pregnancy for signs of withdrawal.

Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ) .

Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects.

Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted.

In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Animal Data Pregnant rats were treated with midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 through 15).

Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose.

All doses produced slight to moderate ataxia.

The high dose produced a 5% decrease in maternal body weight gain compared to control.

Pregnant rabbits were treated with midazolam using intravenous doses of 0.2, 0.6, and 2 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 to 18).

Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose.

The high dose was associated with findings of ataxia and sedation but no evidence of maternal toxicity.

Pregnant rats were administered midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during late gestation and through lactation (Gestation Day 15 through Lactation Day 21).

All doses produced ataxia.

The high dose produced a slight decrease in maternal body weight gain compared to control.

There were no clear adverse effects noted in the offspring.

The study included no functional assessments of the pups, such as learning and memory testing or reproductive capacity.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus.

In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring.

With respect to brain development, this time period corresponds to the third trimester of gestation in the human.

The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits ( see WARNINGS, Pediatric Neurotoxicity, PRECAUTIONS, Pediatric Use, and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY ).

Nursing Mothers Risk Summary There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for midazolam HCl syrup and any potential adverse effects on the breastfed infant from midazolam HCl syrup or from the underlying maternal condition.

Clinical Considerations Infants exposed to midazolam HCl syrup through breast milk should be monitored for sedation, poor feeding and poor weight gain.

A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment for a range of at least 4 to 8 hours after midazolam administration in order to minimize drug exposure to a breastfed infant.

BOXED WARNING

WARNINGS Personnel and Equipment for Monitoring and Depression Midazolam HCl syrup has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings.

Midazolam HCl syrup has been associated with reports of respiratory depression, airway obstruction, desaturation, hypoxia, and apnea, most often when used concomitantly with other central nervous system depressants.

Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that can provide for continuous monitoring of respiratory and cardiac function.

Immediate availability of resuscitative drugs and age- and size-appropriate equipment for ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured [see WARNINGS] .

For deeply sedated patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Risks From Concomitant Use With Opioids Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.

Monitor patients for respiratory depression and sedation [see WARNINGS, PRECAUTIONS/Drug Interactions] .

INFORMATION FOR PATIENTS

Information for Patients To assure safe and effective use of midazolam HCl syrup, the following information and instructions should be communicated to the patient when appropriate: 1.

Inform your physician about any alcohol consumption and medicine you are now taking, especially blood pressure medication, antibiotics, and protease inhibitors, including drugs you buy without a prescription.

Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol during benzodiazepine treatment.

2.

Inform your physician if you are pregnant or are planning to become pregnant.

3.

Inform your physician if you are nursing.

4.

Patients should be informed of the pharmacological effects of midazolam HCl syrup, such as sedation and amnesia, which in some patients may be profound.

The decision as to when patients who have received midazolam HCl syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized.

5.

Midazolam HCl syrup should not be taken in conjunction with grapefruit juice.

6.

For pediatric patients, particular care should be taken to assure safe ambulation.

7.

Effect of Anesthetic and Sedation Drugs on Early Brain Development: Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains.

Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs.

Pregnancy Advise pregnant females that use of midazolam HCl syrup late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy).

Instruct patients to inform their healthcare provider if they are pregnant.

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to midazolam HCl syrup during pregnancy (see Precautions, Pregnancy ).

Nursing Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed.

Instruct breastfeeding patients receiving midazolam to monitor infants for excessive sedation, poor feeding, and poor weight gain, and to seek medical attention if they notice these signs.

A lactating woman may consider pumping and discarding breastmilk for at least 4 to 8 hours after receiving midazolam for sedation or anesthesia to minimize drug exposure to a breastfed infant (see Precautions, Nursing Mothers ).

DOSAGE AND ADMINISTRATION

Midazolam HCl syrup is indicated for use as a single dose (0.25 to 1.0 mg/kg with a maximum dose of 20 mg) for preprocedural sedation and anxiolysis in pediatric patients.

Midazolam HCl syrup is not intended for chronic administration.

Monitoring Midazolam HCl syrup should only be used in hospital or ambulatory care settings, including physicians’ and dentists’ offices that can provide for continuous monitoring of respiratory and cardiac function.

Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured [see WARNINGS] .

For deeply sedated patients, a dedicated individual whose sole responsibility it is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Continuous monitoring of respiratory and cardiac function is required.

Midazolam HCl syrup must be given only to patients if they will be monitored by direct visual observation by a health care professional.

Midazolam HCl syrup should only be administered by persons specifically trained in the use of anesthetic drugs and the management of respiratory effects of anesthetic drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

Patient response to sedative agents, and resultant respiratory status, is variable.

Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes, particularly when coadministered with anesthetic agents, other CNS depressants, and concomitant medications which may potentially cause a more intense and prolonged sedation [see PRECAUTIONS: Drug Interactions] .

This is especially true in pediatric patients.

The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities.

Further recommendations include appropriate presedation fasting.

Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing CNS depression.

Younger (<6 years of age) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring.

When midazolam HCl syrup is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased.

For appropriate patient monitoring, see WARNINGS and : Monitoring.

The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

The recommended dose for pediatric patients is a single dose of 0.25 to 0.5 mg/kg, depending on the status of the patient and desired effect, up to a maximum dose of 20 mg.

In general, it is recommended that the dose be individualized and modified based on patient age, level of anxiety, concomitant medications, and medical need [see WARNINGS and PRECAUTIONS] .

The younger (6 months to <6 years of age) and less cooperative patients may require a higher than usual dose up to 1.0 mg/kg.

A dose of 0.25 mg/kg may suffice for older (6 to <16 years of age) or cooperative patients, especially if the anticipated intensity and duration of sedation is less critical.

For all pediatric patients, a dose of 0.25 mg/kg should be considered when midazolam HCl syrup is administered to patients with cardiac or respiratory compromise, other higher risk surgical patients, and patients who have received concomitant narcotics or other CNS depressants.

As with any potential respiratory depressant, these patients must be monitored for signs of cardiorespiratory depression after receiving midazolam HCl syrup.

In obese pediatric patients, the dose should be calculated based on ideal body weight.

Midazolam HCl syrup has not been studied, nor is it intended for chronic use.

USE OF ORAL DISPENSERS AND PIBA 1.

Remove the cap.

2.

Before inserting the tip of the oral dispenser into bottle adapter, push the plunger completely down toward the tip of the oral dispenser.

Insert tip firmly into opening of the bottle adapter.

3.

Turn the entire unit (bottle and oral dispenser) upside down.

4.

Pull the plunger out slowly until the desired amount of medication is withdrawn into the oral dispenser.

5.

Turn the entire unit right side up and remove the oral dispenser slowly from the bottle.

6.

The tip of the dispenser may be covered with a tip cap, until time of use.

7.

Close bottle with cap after each use.

8.

Dispense directly into mouth.

Do not mix with any liquid (such as grapefruit juice) prior to dispensing.

INSERTION OF PRESS-IN BOTTLE ADAPTER (PIBA) 1.

Remove the cap and push bottle adapter into neck of bottle.

2.

Close the bottle tightly with cap.

This will assure the proper seating of the bottle adapter in the bottle.

DISPOSAL OF MIDAZOLAM HCl SYRUP The disposal of Schedule IV controlled substances must be consistent with State and Federal Regulations.

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